Present State of the Chemistry of Opium and its Future Possibilities

Abstract

The composition of opium is not yet wholly known. From a scientific as well as a commercial point of view, it is necessary to explore further the rare alkaloids it contains and to devise methods of assaying them.

Details

Pages: 7 to 8Creation Date: 1951/01/01

TECHNICAL

The composition of opium is not yet wholly known. From a scientific as well as a commercial point of view, it is necessary to explore further the rare alkaloids it contains and to devise methods of assaying them.

It is generally believed that opium has been very thoroughly examined, so that all its alkaloids are well-known, with the possible exception of one or two present in only infinitesimal quantities.

This is not the case. The chief investigations of opium for minor alkaloids were made over 75 years ago, by Hesse. For the time, the work was magnificent, but it was not actually complete. Moreover, the statements now in the books about the characteristics of at least some eight or ten of the alkaloids that were discovered, are so meagre and even inaccurate that it is quite impossible to recognize these alkaloids as they are analytically isolated, without exhaustive investigations-even knowing that they come from opium, and even though they are actually present in amounts many times as great as the minute percentages attributed to them.

For example, a minor phenolic alkaloid, which accompanies morphine in most extractions, can be isolated from less than half a gram of opium, so as to be easily recognized by colour reactions. In fact, it probably constitutes at least 0.1 per cent, possibly 0.2 per cent, of many opiums. It is titratable and its presence thus introduces an error of about 1 to 2 per cent into many morphine assays by extractive methods (irrespective of other possible errors). It may be codamine. Codamine is said to give a "dark green" colour with nitric acid, gradually becoming lighter; the deep green colour with nitric acid is supposed to distinguish it from any of the other opium alkaloids. With the extracted alkaloid, nitric acid does indeed strike green, but this colour instantly vanishes, and a strong yellow-brown promptly develops.

The reaction found is of the glaucine type. In fact, this alkaloid, which far exceeds the percentage attributed to codamine (only 0.0033 per cent), in colour reactions much more closely resembles glaucidine-a minor phenolic alkaloid isolated from Papaver orientale by Gadamer and Klee-than it does the codamine described by Hesse.

Moreover, there is another minor phenolic alkaloid in opium that also gives the nitric acid reaction and other glaucidine-type reactions. Perhaps it, instead of the alkaloid that so closely accompanies morphine, is codamine, though the description of the properties of codamine fits even less well in this case. At any rate it seems that at least one of these alkaloids has never been "officially" discovered.

One minor alkaloid of opium is easily characterized by its property of yielding an intense purplish-red colour when its solution in dilute mineral acid is tested. In the lists of opium alkaloids in books, it appears three times under different names: rhoeadine, porphyroxine, and meconidine. The true rhoeadine, alkaloid of Papaver rhoeas, does not exist in opium. The properties ascribed to "porphyroxine" are all wrong; the last "porphyroxine" (Rakshit's) was probably impure codeine. Hesse's "meconidine" was never obtained in crystalline form and actually must have been a mixture of phenolic alkaloids. The real red-turning alkaloid has been isolated in crystalline form by the writer, but only on a rather small scale by extractive methods, and no determination of the elementary or constitutional formula has yet been made. (See E/CN.7/ll7, 14 April 1948, part II D, Some Minor Alkaloids of Opium, Alkaloid I, "Porphyroxine-Meconidine".)

In working up about 2 pounds of opium (primarily for "porphyroxine-meconidine") a minor phenolic alkaloid was obtained which was probably laudanine. However, it: was extractable by chloroform from alkali solution, contrary to the statements about laudanine.

Of seven minor phenolic alkaloids either isolated or otherwise noted in this investigation, not a single one except the "porphyroxine-meconidine" (which was wrongly described) could be recognized, with any complete assurance, as being a previously-named alkaloid of opium.

To remedy this situation intensive investigation is needed. A thorough investigation on no more than 10 kilograms of opium would most probably show what alkaloids, of those that can be recognized in even a few grams of opium by solvent-extraction methods and colour tests, are to be regarded as having been already discovered and named, even if not correctly described in all respects. A more extensive investigation ought to be made, for the reason that at the same time several new phenolic alkaloids could almost certainly be discovered.

Particular attention ought to be given also to water-soluble bases that are extracted but very slightly, if at all, by ether and other immiscible solvents. The neglect in this field may be illustrated by a related case that has now been clarified, but only recently. Selmi, in 1876, wrote of the discovery of an "alkaloid" in the green capsules of Papaver rhoeas which, in its Solubility in amyl alcohol but not in most immiscible solvents, and in certain reactions, including the yielding of crystals with iodine-HI solution, showed certain similarities to morphine with respect to properties and reactions used in toxicological identifications. He specifically said that it was not morphine. Hesse, previously the discoverer of rhoeadine (alkaloid of Papaver rhoeas), thereupon reexamined Papaver rhoeas, but in such a way as to fail completely even to discover what Selmi was talking about- which seems to have been, so far as a nitrogenous base is concerned, a very conspicuous content of choline. This episode appears in a number of books of reference which refer to Selmi as having claimed to find morphine in Papaver rhoeas, and the claim refuted by Hesse. (See The Opium Poppyand Other Poppies, issued by the U.S. Treasury Department, Bureau of Narcotics, Washington, 1944; pages 57-58, 77-78.)

Returning to opium, there is ample evidence of the presence of nitrogenous bases not included within the scope of the original searches for alkaloids. Because of the poor solubility of morphine in any very useful immiscible solvent, extractive separations of morphine are generally made with a combination of solvents such as chloroform-ethanol, chloroform-isopropanol, or benzene-isopropanol. By reason of some solubility in ethanol or isopropanol, these water-soluble compounds of basic nitrogen usually contaminate the morphine extract. They do not seem to be titrated with the morphine and may be either very feeble bases or, perhaps, strong bases the salts, of which are partially extracted, while the bases themselves are either volatile or not even set free by ammonia.

In examining young seedlings of the opium poppy, the writer found one such compound rather conspicu- ously present. Crystals with a gold bromide reagent could be obtained to characterize it, but it was never identified nor even further studied. Could it be the precursor of morphine?-for very probably the plant constructs morphine out of some simpler compound.

Here we may note that Annett, Sen, and Singh reported that, while the opium from successive scarifications shows a rapid and large fall in morphine content, the percentage of nitrogen remains practically constant. ("Investigations on Indian Opium, No. 1", Memoirs of the Department of Agriculture in India, vol. 6, No. 1, pages I to 154.) The substance or substances making up the difference are unknown.

New and really thorough investigations of opium for its alkaloids and other nitrogenous bases are highly desirable from all points of view: scientific, practical, commercial, analytical, chemical, botanical. The pure scientist will doubtless be rewarded more than others, but the need is evident from purely analytical researches. Since former scientific researches were chiefly on Turkish opium, it is probable that new alkaloids can most easily be discovered, or found in greater quantity, in some other kind, such as Iranian or Indian. Minimum requirements for the amount of opium are not so excessive as might be supposed: considering the development of microchemistry, it is possible that 10 kilograms now will go nearly as far in experienced hands as a ton in Hesse's day. The Canadian chemist of the Organic Chemistry and Narcotic Section, Food and Drug Divisions, Department of National Health and Welfare, who is already collaborating in the United Nations inquiry on the methods of determining the origin of seized opium by chemical and physical means, has indicated that he intends to make such fundamental investigations as he can, particularly for the minor phenolic alkaloids, old and new. There seems to be room for other investigations which would overlap his only slightly or not at all.

Nothing has been said in the foregoing about the non-nitrogenous constituents of opium. Some of the known non-nitrogenous compounds, for example meconic acid and meconin, are of considerable interest, and practically are known only from opium and the opium poppy plant. The water-soluble constituents of poppy chaff, after extraction of the alkaloids, have been studied by Karrer and Schmid (Helvetica Chimica Acta, 1945, 28, 722); these constituents may or may not be about the same in opium.

Little is known about the opium fat or wax, the odorous substances present, the coloured compounds-not present in the opium (poppy juice) as it comes from the plant, etc. It is very probable that investigation of the non-nitrogenous compounds of opium would also be interesting, valuable, and scientifically rewarding.